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Many Ebola vaccine candidates against Ebola had been developed in the decade prior to 2014, but none has yet been approved for clinical use in humans. Several promising vaccine candidates have been shown to protect nonhuman primates (usually macaques) against lethal infection. These include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and human parainfluenza (HPIV-3) vectors, and virus-like nanoparticle preparations. Conventional trials to study efficacy by exposure of humans to the pathogen after immunization are obviously not feasible in this case. For such situations, the FDA has established the “Animal Efficacy Rule” allowing licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety and a potentially potent immune response (antibodies in the blood) from humans given the vaccine. Clinical trials involve the administration of the vaccine to healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage.

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cAd3-EBO Z
In September 2014, two Phase 1 clinical trials began for the vaccine cAd3-EBO Z, which is based on an attenuated version of a chimpanzee adenovirus (cAd3) that has been genetically altered so that it is unable to replicate in humans. The cAd3 vector has a DNA fragment insert that encodes the Ebola virus glycoprotein, which is expressed on the virion surface and is critical for attachment to host cells and catalysis of membrane fusion. It was developed by NIAID in collaboration with Okairos, now a division of GlaxoSmithKline. For the trial designated VRC 20, 20 volunteers were recruited by the NIAID in Bethesda, Maryland, while three dose-specific groups of 20 volunteers each were recruited for trial EBL01 by University of Oxford, U.K. Initial results released in November 2014 were promising, with the vaccine appearing to be both safe and effective, with all 20 volunteers developing antibodies against Ebola. In December 2014, University of Oxford expanded the trial to include a booster vaccine based on MVA-BN, a strain of Modified vaccinia Ankara, developed by Bavarian Nordic, to investigate whether it can help increase immune responses further. The trial which has enrolled a total of 60 volunteers will see 30 volunteers vaccinated with the booster vaccine. As of April 2015, Phase 3 trial with a single dose of cAd3-EBO Z begins in Sierra Leone after a successful Phase 2 study in West Africa countries.

VSV-EBOV
A vaccine based on the vesicular stomatitis virus which was genetically modified to express a surface glycoprotein of Zaire Ebola virus, called VSV-EBOV, has been developed by the Public Health Agency of Canada, with development subsequently taken over by Merck Inc. In October 2014, the Wellcome Trust announced the start of multiple trials in healthy volunteers in Europe, Gabon, Kenya, and the USA. The trial was temporarily halted in December 2014 due to possible adverse effects, but subsequently resumed. As of April 2015, a Phase 3 trial with a single dose of VSV-EBOV began in Liberia after a successful Phase 2 study in the West Africa country. On 31 July 2015, preliminary results of a Phase 3 trial in Guinea indicated that the vaccine is "highly efficacious and safe." The trial used a ring vaccination protocol that first vaccinated all the closest contacts of new cases of Ebola infection either immediately or after 21 days. Because of the demonstrated efficacy of immediate vaccination, all recipients will now be immunized immediately. Ring vaccination is the method used in the program to eradicate smallpox in the 1970s. The trial will continue to assess whether the vaccine is effective in creating herd immunity to Ebola virus infection.

Ad26.ZEBOV/ MVA-BN
Johnson & Johnson has developed an Ebola vaccine at its Janssen Pharmaceutica Company. The regimen consists of two vaccine components (first vaccine as prime, followed by a second vaccine as boost) that are based on AdVac technology from Crucell Holland B.V., which is part of Janssen, and the MVA-BN technology from Bavarian Nordic. The Ad26.ZEBOV is derived from human adenovirus serotype 26 (Ad26) expressing the Ebola virus Mayinga variant glycoprotein while the second component MVA-BN is the Modified Vaccinia Virus Ankara - Bavarian Nordic (MVA-BN) Filo-vector. This product commenced Phase 1 clinical trial at the Jenner Institute in Oxford during January 2015. The preliminary data indicated the prime-boost vaccine regimen elicited temporary immunologic response in the volunteers as expected from vaccination. The Phase 2 trial enrolled 612 adult volunteers and commenced in July 2015 in United Kingdom and France. A second Phase 2 trial, involving 1,200 volunteers, has been initiated in Africa with the first trial commenced in Sierra Leone in October 2015.

Ebola GP vaccine
At the 8th Vaccine and ISV Conference in Philadelphia on 27−28 October 2014, Novavax Inc. reported the development in a "few weeks" of a glycoprotein (GP) nanoparticle Ebola virus (EBOV GP) vaccine using their proprietary recombinant technology. A recombinant protein is a protein whose code is carried by recombinant DNA. The vaccine is based on the newly published genetic sequence of the 2014 Guinea Ebola (Makona) strain that is responsible for the current Ebola disease epidemic in West Africa. In "preclinical models", a useful immune response was induced, and was found to be enhanced ten to a hundred-fold by the company's "Matrix-M" immunologic adjuvant. A study of the response of non-human primate to the vaccine had been initiated. Attractive features of such a vaccine could be no need for frozen storage, and the possibility of rapid scaling to manufacture of large dose quantities. Novavax has completed 2 primate studies on baboons and macaques and has initiated a Phase 1 clinical trial in Australia in February 2015. The top line Phase 1 human trial results showed that the adjuvanted Ebola GP Vaccine was highly immunogenic at all dose levels. The adjuvanted two-dose regimens induced Ebola anti-GP antibody geometric mean responses between 45,000 and 70,000 ELISA units, representing a 500 to 750-fold rise over baseline at day 35.

Nasal vaccine
On November 5, 2014, the Houston Chronicle reported that a research team at the University of Texas-Austin developed a nasal spray Ebola vaccine, which the team had been working on for seven years. In a test, 100 percent of monkeys given the vaccine were saved from the virus. When researchers tested an injected version of the same vaccine on monkeys, half of the monkeys were saved. However, as of early November 2014, the team was running out of money. Without further funding, it will not be able to conduct human trials, which is the next step in the research process.

Vaxart tablet
Vaxart Inc. is developing a vaccine technology in the form of a temperature-stable tablet which may offer advantages such as reduced cold chain requirement, and rapid and scalable manufacturing. In January 2015, Vaxart announced that it had secured funding to develop its Ebola vaccine to Phase 1 trial.

Recombinant adenovirus type-5 vector-based Ebola vaccine
In late 2014 and early 2015, a study funded by the Beijing Institute of Biotechnology, China National Science and Technology and Tianjin CanSino Biotechnology and led by Feng-Cai Zhu conducted a double-blind, randomized Phase 1 trial that utilized a placebo in the Jiangsu Province of China. The trials were unique in that the vaccine expressed the glycoproteins of the 2014 strain of the virus using a new adenovirus vector, rather than that of the 1976 strain. The vaccine was found to provoke immune response within 14 days and to have high safety and immunogenicity at high doses.

Whole virus vaccine
A study published in Science during March 2015 demonstrates that vaccination with a weakened form of the Ebola virus provides some measure of protection to non-human primates. The new vaccine relies on a strain of Ebola called EBOVΔVP30, which is unable to replicate.